This mentored training proposal will provide the applicant (Clare Wilhelm, Ph.D.) with training and skills in immunology, gene expression profiling, and alcohol vapor inhalation methods that will facilitate his transition to an independent scientist, while exploring timely and critical isses related to alcohol abuse, neuroinflammation and neurotoxicity. Candidate development will be accomplished through directed readings and discussions with the applicant's mentors, didactic studies, and hands on experimental training related to models of alcohol exposure, gene expression profiling, and immunohistochemistry. Upon completion, the applicant will be well positioned to pursue his long-term career goal of developing more efficacious treatments for alcohol and drug abuse. He is committed to a career in academic research and aspires to develop his own independent research program. The combined environments of the Portland VA Medical center (PVAMC) and Oregon Health & Science University (OHSU) provide an ideal environment for this proposal. Specific course work available at OHSU is highly relevant to the proposed project and will contribute to the applicant's development. The research environments of these venues are particularly strong, with alcohol-, methamphetamine-, and Alzheimer's disease research centers and the availability of numerous potential collaborators and consultants. Distinguished local departments are also available related to this project including: Behavioral Neuroscience, Neurology, Psychiatry and Molecular Microbiology and Immunology. The mentors (Drs. Wiren and Quinn) and consultants (Drs. Loftis and Hinrichs) possess the backgrounds and experiences in alcohol abuse, sex and genetic differences, gene expression profiling, immunology, neuroinflammation and neurotoxicity that will ensure the success of the scientific and career development plans. Alcohol abuse/dependence remains one of the most costly diseases in the U.S.A. and is particularly common in the veteran population. Effective treatments are lacking. Individuals that abuse alcohol often develop brain damage which can persist long after drinking has subsided, contribute to relapse and reduce treatment efficacy. Studies in mice have identified differences in neurotoxicity following chronic alcohol exposure. Humans with an alcohol abuse history exhibit increased activation of neuroinflammatory cascades in several brain areas. Our preliminary data suggests distinct neuroimmune differences between animals exhibiting neurotoxicity and those that do not. We hypothesize that alcohol-induced neurotoxicity is the result of activation of neuroinflammatory cascades in response to alcohol exposure. To explore this hypothesis, we will use mouse models of alcohol-induced neurotoxicity (female withdrawal seizure prone (WSR) animals) and alcohol-induced neuroprotection (male WSR animals). Neurotoxicity and neuroinflammation will be examined using immunohistochemistry to examine infiltration of peripheral immune cells, gene expression profiling to determine changes in neuronal integrity, and hematoxylin and eosin and silver staining to examine neurotoxicity. This project will provide important new information on alcohol-induced changes in brain neurochemistry that may result in the identification or development of novel therapeutics to treat alcohol abuse/dependence disorders. PUBLIC HEALTH RELEVANCE: Alcohol abuse has tremendous socioeconomic costs. The veteran population exhibits an increased propensity to develop abuse/dependence disorders. This proposal will lay the groundwork for the development of new immune-based therapeutics for alcohol abuse. In addition, this study will provide critical new insight into the role of neuroinflammation in alcoho-induced neurotoxicity. The identification of new pathways to heal brain damage induced by chronic alcohol abuse is critically needed.